Research into long term neurological conditions: Progress and challenges

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Research into long term neurological
conditionsProgress and challenges

• Hampshire Neurological Alliance Launch
• 16th March 2009
• Professor Alan Thompson, UCL Institute of
  Neurology

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Prevalence (compared to other brain disorders)
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High cost per patient
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Recommendations for Action

• Gain commitment from decision-makers
• Increase public and professional awareness
• Minimise stigma and eradicate discrimination
• Strengthen neurological care within existing
  health systems
• Incorporate Rehabilitation
• Develop national capacity and international
  collaboration
• Define research priorities

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Research three broad areas

• Cause/Pathophysiology
• Cure Treatments
• Management/Service delivery - Rehabilitation

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Dementia

• A major public health and research imperative
• 700,000 cases of dementia in the UK
• 400,000 with Alzheimers disease

1906 Alzheimer Neurofibrillary tangles
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Projected numbers of people with dementia in the
UK 1m by 2025
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Multiple Sclerosis
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Multiple Sclerosis The Facts

• Inflammatory demyelinating condition of unknown
  aetiology
• Relapsing remitting course in majority of
  patients becoming progressive over time
• More common in females than males (21)
• Prevalence of 1 in 1,000
• 90,000 affected in UK, 350,000 in Europe
• Most common age of presentation 25 to 30
• Complex, unpredictable condition
• Huge impact on all those affected by it

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Cause/Pathophysiology
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Structural features of the MS lesion
Inflammatory demyelination
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Autoimmune demyelination
Pattern I
T cells CD4/CD8
Antibody/ complement-mediated
T cell/ macrophage- mediated
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Oligodendrocyte dystrophy
Pattern III
T cells CD4/CD8
Distal oligodendrogliopathy apoptosis
Primary oligodendrocyte degeneration
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Pathology of multiple sclerosis

• MS is not only a disease with focal white matter
  lesions
• Global involvement
• Involvement of the Normal Appearing White Matter
• Pathology also seen in the Cortex

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MS Lesions - MRI
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Grey matter damage in MS
Bö et al., Arch Neurol 2007 Geurts et al., JNEN
2007 Geurts Barkhof 2008
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Genome-wide Association studies

• Amyotrophic Lateral Sclerosis
• Parkinsons disease
• Alzheimers Disease
• Multiple Sclerosis
• Stroke

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Cure/Treatments

• Better diagnosis
• Trial design
• Outcome measures
• New targets
• Phenotype/Genotype studies

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How is MS Diagnosed?

• CLINICAL DIAGNOSIS!
• Two or more areas involved
• Two or more attacks (relapses)
• Other conditions excluded

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BARKHOF CRITERIA (1997)

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CIS patient at baselineDIS (Barkhof) criteria
positive
Case Study 4 37 year old lady with left optic
neuritis 4 periventricular lesions, 1 enhancing
subcortical lesion
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CIS patient At 3 monthsMcDonald MRI criteria
positive
New ventricular T2 lesions
New enhancing lesion
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TREATMENT

• Measuring Outcome

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Definitions

• Patient-Reported Outcomes
• Aspects of outcome known only to the patient
• Patient-reported outcome measures (PROMs)
• The tools we use to measure these outcomes

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• Symptoms relief
• Upper back pain
• Satisfaction
• With care in the office or hospital
• Quality of life
• Body image after breast reconstruction

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FDA guidance document
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For more information...
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Diagnostic and research methods MRI in AD
H
Time 0 18months 36months
Serial coronal MRI of an individual with
initially mild AD
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Investigations of patients with MND
Tractography
TBSS
Regions of interest
FA is lower in PLS than ALS
FA is lower in ALS with greater dis. progression
Brain 2006
HBM 2009
JNNP 2003
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Treatment of MS

• Immunomodulation
• Suppressing inflammation/demyelination
• Neuroprotection
• Remyelination and repair
• Neuroplasticity / Neurorehabilitation

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Natalizumab A Humanized, Monoclonal Antibody
(mAb) Against ?4 Integrins
Complementarity-Determining Regions ((CDRs

• CDR grafted from murine Ab
• Human IgG4 framework
• Retains full potency

Human IgG4 Framework
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Targeting blood-brain barrier
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Annualized Relapse Rate Pre-specified Primary
Endpoint
1.0
0.9
0.8
0.7
0.6
0.5
Annualized Relapse Rate (95 CI)
0.4
0.3
0.2
0.1
0.0
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Natalizumab

• NICE Guidance 2007
• Rapidly evolving severe (RES) relapsing remitting
  MS at least two relapses over a year and active
  MRI scan

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Under Investigation
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AlemtuzamabNew hope for multiple sclerosis
sufferersResearch indicates drug not only stops
the disease from advancing but may alsorestore
lost function in many patients
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FTY720 (FINGOLIMOD) Mode of Action
Sphingosine 1-phosphate (S1P) receptor modulator
Multiple Sclerosis

• FTY720 traps circulating lymphocytes in
  peripheral lymph nodes

FTY720-P
T cell
LN
? internalizes S1P1 blunting response to
chemotactic signals? blocks lymphocyte egress
from LN while sparing immune surveillance by
peripheral memory T cells(FINGOLIMOD)

• reduces T cell infiltration in the CNS

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Primary endpoint total cumulative number of Gd
lesions Months 06
Placebo (n 81)
Lesion number
FTY 1.25 mg (n 83)
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FTY 5 mg (n 77)
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14.8
-43
-62
12
10
8
8.4
6
-40
5.7
5
4
-80
3
2
1
0
11.6
22.5
23.7
0114
0182
091
Mean SD
Median range
p lt 0.001 FTY 1.25 mg vs placebo p 0.006 FTY 5
mg vs placebo p 0.212 FTY 1.25 mg vs FTY 5 mg
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Months 06 annualized relapse rate
Annualized relapse rate
1.0
0.8
0.77
0.6
-55
-53
0.4
0.36
0.35
0.2
0.0
Placebo(n 92)
FTY 1.25 mg(n 93)
FTY 5 mg(n 92)
p 0.009 FTY 1.25 mg vs placebo p 0.014 FTY 5
mg vs placeboPopulation core ITT
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NEUROPROTECTION

• Sodium Channel Blockers
• Lamotrogine
• Topiramate
• Carbamazepine
• Phenytoin
• Flecanide (S.E.)
• NMDA Antagonists
• Riluzole
• Memantine

• NOS Inhibitors
• Minocycline
• NO Scavengers
• Uric acid etc.
• Cannabinoids

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Deep Brain Stimulation
Deep Brain Stimulation (DBS) involves the precise
placement of minute electrodes in very specific
regions of the brain through which tiny
electrical current can be delivered. These
electrodes are connected to a battery placed
under the skin of the chest or abdominal wall.
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Who can benefit from DBS?

• Parkinsons disease patients suffering from
• Medication wearing off, Drug induced involuntary
  movements (Dyskinesias), Tremor
• Dystonia patients
• not helped sufficiently by medication or
  Botulinum toxin injections
• Patients with other tremor types
• Essential tremor, Dystonic tremor
• Sites
• Subthalamic nucleus (STN) gt
• Pedunculopontine Nucleus (PPN)

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FMRI vs Residual visual function at baseline
Right lateral occipital complex
Stronger fMRI response associated with greater
residual visual function after variance
attributed to structural factors
removed Therefore probably adaptive
reorganization.
Left lateral occpital complex
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GENERAL MANAGEMENT and SERVICE DELIVERY
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NSF for long term neurological conditions

• Giving people choice, through services planned
  and delivered around their individual needs
• Supporting people to live independently and play
  their full part in society
• Partnership between health and social services

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Why have an NSF for Neurological Conditions?

• Provide better services across the country
• Improve equity of access
• Address long waiting times/waiting lists
• Increase numbers of appropriately trained and
  experienced staff
• Improve social services support for people living
  with long-term condition

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Key principles of the NSF

• Person-centred care and choice
• Integrated care-planning and inter-agency,
  co-ordinated service provision
• Prompt diagnosis, referral, investigations and
  specialist treatment
• Rehabilitation, support in the community and
  vocational rehabilitation
• Support for families and carers
• Choice over end of life care

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National Dementia Strategy 2009

• To improve, awareness, diagnosis and care in
  dementia leading to
• Expansion of investigational and care services
• Improved capacity to deliver education and
  training
• Major research opportunities

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Translational potential

• Bringing CSF and MRI biomarkers together with
  cognitive and clinical assessments
• Improving early diagnosis
• Effective differential diagnosis
• Measuring progression in disease modifying trials

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Management of MS

• Emphasis on self-management
• Concept of wellness diet, exercise etc.
• Accurate up-to-date information
• Access to appropriate expertise
• Treatment of acute events
• Treatment strategies for condition itself

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1-1 education
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Management of MS

• Multidisciplinary rehabilitation programmes
• Individual therapy e.g. physiotherapy
• Symptomatic treatment
• fatigue, spasticity and pain
• Complementary therapies

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CAMS OutcomesAshworth negative CRS positive

• Category Rating Scales
• Perceived Benefit
• Spasticity (p 0.01)
• Sleep (p 0.025)
• Pain (p 0.002)
• Spasm (p 0.038)
• No Benefit
• Irritability
• Depression
• Tiredness

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Sustained release fampridine in MS
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FUNDING
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Long Term Neurological Conditions

• Research Initiative

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NSF LTNC RI

• Defining the palliative care needs of people with
  late stage Parkinsons disease, multi system
  atrophy and progressive supranuclear plasy
  (Kings)
• Needs and experiences of services by individuals
  with progressive disabling neurological disorders
  and their carers a bench- marking study
  (Oxford)
• Integrated care for people with long term
  neurological condition s (York)

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NSF LTNC RI

• 4. Transition to adulthood the experiences and
  needs of young men with Duchenne Muscular
  Dystrophy
• 5. Long term individual fitness enablement
  (LIFE)
• MS, Muscular dystrophy, Parkinsons disease,
  MND
• 6. Quality Neurology develop and evaluate an
  audit methodology, with service users at the
  centre of assessment process

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Unravelling NeurodegenerationOctober 2008

• Partnership between Wellcome Trust and MRC
• Strategic Awards in Neurodegenerative Diseases
• 30 million strategic initiative aims to
  stimulate high-quality, collaborative research
  that will advance knowledge of neurodegenerative
  diseases through interdisciplinary approaches.

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MRC call for MND

• October 2008